Early lung tumorigenesis is poorly understood at the molecular level. Consequently, no validated molecular marker is currently available for lung cancer risk assessment or evaluation of therapeutic efficacy. We previously demonstrated that certain genetic alterations commonly found in lung cancers might occur in normal-appearing bronchial epithelium of smokers. Altered expression patterns of tumor suppressor genes/oncogenes could also be detected in the bronchial epithelium of smokers. Recently, we found that DNA methylation status in promoter regions of genes involved in tumorigenesis could be altered, not only in lung tumors but also in the bronchial cells of smokers without cancer, resulting in transcriptional repression or activation of these genes. Recent advances in human genome project and high-throughput technologies provide opportunity to accelerate discovery of biomarkers for cancer risk assessment and evaluation of therapeutic efficacy. We hypothesize that substantial molecular alterations occur in airway of smokers, which causes "field defect" and associates with an increased lung cancer risk in this population. As a result, these molecular alterations critical in the initiation of transformation and early progression may predict lung cancer risk and can be used as intermediate endpoints to assess efficacy of chemopreventive agents. Three specific aims are proposed: (1) To identify molecular alterations in smoking damaged lungs and determine their role in assessing efficacy of chemopreventive agents. We will focus on molecular abnormalities that involve critical pathways and can be frequently detected in the bronchial epithelial cells in smokers. Potential differences between current and former smokers will also be analyzed. (2) To determine the role of easily accessible tissues as surrogate materials in evaluating lung damages and chemopreventive effects in the lung. We will determine molecular alterations in sputum and oral brushes in smokers and more importantly to see if potential drug effects in these specimens may reflect those in lung bronchial epithelium. (3) To identify novel biomarkers for risk assessment and evaluation of effects of chemoprevention. In this exploratory aim, we will identify proteins abnormally expressed in carcinogen damaged lungs with high risk to develop lung cancer as well as proteins modulated by chemopreventive agents. We believe that the success of this project will significantly improve our understanding of early lung carcinogenesis at the molecular level and provide useful molecular markers for lung chemoprevention.